Cancer has become one of the major global health concerns and remains as the second cause of mortality after cardiovascular diseases. Cancer is a group of malignancies and characterized by uncontrolled cell growth in which cells lose their communication with surroundings and ignore the cell signaling. Chemoresistance is an important phenomenon associated with the cell division. In addition, safety profile and side effects are the major concerns with anticancer drugs. Therefore, the development of novel agents with increased efficacy while reducing the side effects will encourage the researchers towards the drug design and development.
Nuclear condensation and DNA fragmentation with various biological and cytological processes are involved in apoptosis. The extrinsic pathway of apoptosis involves binding of death activators to receptors such as tumor necrosis factor TNF-Rα and an intrinsic or mitochondrial pathway involves the initiation of apoptosis by chemotherapeutic agents as well as genotoxic stress and other death stimuli. (How cells die: apoptosis pathways. Zimmermann, K. C.; Green, D. R. J. Allergy. Clin. Immunol. 2001, 108, S99-S103). Caspases are a family of cysteine protease and are known to play a critical role for the initiation and execution of apoptosis (Caspase function in programmed cell death. Kumar, S. Cell Death Differ. 2007, 14, 32-43). Amongst the caspases, caspase-3, -6, and -7 are key effector caspases that cleave multiple protein substrates in cells ° leading to irreversible cell death (Caspases: Key mediators of apoptosis. Thornberry, N. A. Chem. Biol. 1998, 5, R97-R103).
E7010 (1, N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzene sulfonamide, FIG. 1B), an orally active sulfonamide antitumor agent that is currently in a Phase I clinical trial, showed rather consistent growth-inhibitory activities against a panel of 26 human tumor cell lines. This compound causes cell cycle arrest and apoptosis in M phase and is shown to exhibit microtubule assembly owing to its reversible binding to the colchicines binding site on tubulin. E7010 also exhibited good in vivo antitumor activity against various rodent tumor and human tumor xenograpts and reached the clinical studies phase II it caused a dose-dependent increase in the percentage of mitotic cells in parallel with a decrease in cell proliferation (Mechanism of action of E7010, an orally active sulfonamide antitumor agent: inhibition of mitosis by binding to the colchicine site of tubulin. Yoshimatsu, K.; Yamaguchi, A.; Yoshino, H.; Koyanagi, N.; Kitoh, K. Cancer Res. 1997, 57, 3208-3213 and Mauer, A. M.; Cohen, E. E.; Ma, P. C.; Kozloff, M. F.; Schwartzberg, L.; Coates, A. I.; Qian, J.; Hagey, A. E.; Gordon, G. B. J. Thorac. Oncol., 2008, 3, 631-636). N-(2-Anilino-pyridyl) moiety, which exhibited interesting antitumor activity and some of these analogues are undergoing clinical trials (Novel sulfonamides as potential, systemically active antitumor agents. Yoshino, H.; Ueda, N.; Niijima, J.; Sugumi, H.; Kotake, Y.; Koyanagi, N.; Yoshimatsu, K.; Asada, M.; Watanabe, T.; Nagasu, T. J. Med. Chem. 1992, 35, 2496-2497); (In vivo tumor growth inhibition produced by a novel sulfonamide, E7010, against rodent and human tumors. Koyanagi, N.; Nagasu, T.; Fujita, F.; Watanabe, T.; Tsukahara, K.; Funahashi, Y.; Fujita, M.; Taguchi, T.; Yoshino, H.; Kitoh, K. Cancer Research. 1994, 54, 1702-1706); (Synthesis and structure-activity relationships of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids as antitumor agents. Part 2. Tsuzuki, Y.; Tomita, K.; Shibamori, K.; Sato, Y.; Kashimoto, S.; Chiba, K. J. Med. Chem. 2004, 47, 2097-2109).
Carbonic anhydrase (CA) plays an essential role in facilitating the transport of carbon dioxide and protons in the intracellular space, across biological membranes and in the layers of the extracellular space. Ethoxazolamide (2 shown in FIG. 1B) a benzothiazole sulfonamide inhibits CA activity in proximal renal tubules to decrease reabsorption of water, sodium, potassium, bicarbonate. Ethoxazolamide and its structurally similar related analoges have shown to exhibit excellent anticancer activity by inhibiting CA and some of them are in clinical trials (The compound 6-ethoxy-1,3-benzothiazole-2-sulfonamide (ethoxazolamide) showed good antitumor profile. Vullo, D.; Franchi, M.; Gallori, E.; Antel, J.; Scozzafava, A.; Supuran, C. T. J. Med. Chem. 2004, 47, 1272-1279). Benzothiazoles are known to possess interesting anticancer activity (Antitumor benzothiazoles. 7. Synthesis of 2-(4-acylaminophenyl) benzothiazoles and investigations into the role of acetylation in the antitumor activities of the parent amines. Chua, M. S.; Shi, D. F.; Wrigley, S.; Bradshaw, T. D.; Hutchinson, I.; Shaw, P. N.; Barrett, D. A.; Stanley, L. A.; Stevens, M. F. J. Med. Chem. 1999, 42, 381-392); (Antitumor benzothiazoles. 8. Synthesis, metabolic formation, and biological properties of the C- and N-oxidation products of antitumor 2-(4-aminophenyl) benzothiazoles. Kashiyama, E.; Hutchinson, I.; Chua, M. S.; Stinson, S. F.; Phillips, L R.; Kaur, G.; Sausville, E. A.; Bradshaw, T. D.; Westwell, A. D.; Stevens, M. F. J. Med. Chem. 1999, 42, 4172-4184); (Antitumor benzothiazoles. 26. 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (GW 610, NSC 721648), a simple fluorinated 2-arylbenzothiazole, shows potent and selective inhibitory activity against lung, colon, and breast cancer cell lines. Mortimer, C. G.; Wells, G.; Crochard, J. P.; Stone, E. L.; Bradshaw, T. D.; Stevens, M. F.; Westwell, A. D. J. Med. Chem. 2006, 49, 179-185. (N-(cycloalkylamino) acyl-2-aminothiazole inhibitors of cyclin-dependent kinase 2. N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidine carboxamide (BMS-387032), a highly efficacious and selective antitumor agent. Misra, R. N.; Xiao, H. Y.; Kim, K. S; Lu, S.; Han, W. C.; Barbosa, S. A.; Hunt, J. T.; Rawlins, D. B.; Shan, W.; Ahmed, S. Z.; Qian, L.; Chen, B. C.; Zhao, R.; Bednarz, M. S.; Kellar, K. A.; Mulheron, J. G.; Batorsky, R.; Roongta, U.; Kamath, A.; Marathe, P.; Ranadive, S. A.; Sack, J. S.; Tokarski, J. S.; Pavletich, N. P.; Lee, F. Y.; Webster, K. R.; Kimball, S. D. J. Med. Chem. 2004, 47, 1719-1728); (Novel benzothiazolyl urea and thiourea derivatives with potential cytotoxic and antimicrobial activities. Abdel-Rahman, H. M.; Morsy, M. A. J. Enzyme Inhib. Med. Chem. 2007, 22, 57-64). 2-(4-Aminophenyl) benzothiazoles and 2-(4-hydroxyphenyl) benzothiazoles are novel class of potent and selective antitumour agents and found to exhibit antitumor activity particularly against certain breast carcinoma cell lines in vitro (e.g., MCF-7, MDA 468, IC50<1 nM) to be promising anticancer activity (Antitumor Benzothiazoles. 3. Synthesis of 2-(4-Aminophenyl) benzothiazoles and evaluation of their activities against Breast Cancer Cell Lines in vitro and in vivo. Shi, D. F.; Bradshaw, T. D.; Wrigley, S.; McCall, C. J.; Lelieveld, P.; Fichtner, I.; Stevens, M. F. J. Med. Chem. 1996, 39, 3375-3384); (Antitumor Benzothiazoles. 14. Synthesis and in vitro biological properties of fluorinated 2-(4-Aminophenyl)benzothiazoles. Hutchinson, A.; Chua, M.; Browne, H. L.; Trapani, V.; Bradshaw, T. D; Westwell, A. D; Stevens, M. F. J. Med. Chem. 2001, 44, 1446-1455).
Many synthetic analogs containing sulfonamides with incorporated hydrazine moieties (3 shown in FIG. 1B) have shown promising anticancer activity (Synthesis of a new class of 2-anilino substituted nicotinyl arylsulfonylhydrazides as potential anticancer and antibacterial agents. Kamal, A.; Khan, M. N. A.; Reddy, K. S.; Rohini, K. Bioorg. Med. Chem. 2007, 15, 1004-1013) Keeping this aspect in mind, 2-amino benzothiazole rings system has been linked to N-(2-anilino-pyridyl) scaffold, therefore, the newly designed and synthesized molecules comprising of benzothiazoles and 2-anilinopyridyl moiety could possess promising anticancer activity: Additionally, these are structurally simple small molecules.